National Cancer Institute

at the National Institutes of Health

Melanoma Treatment (PDQ®)

Health Professional Version

Table of Contents

General Information About Melanoma

Melanoma is a malignant tumor of melanocytes, which are the cells that make the pigment melanin and are derived from the neural crest. Although most melanomas arise in the skin, they may also arise from mucosal surfaces or at other sites to which neural crest cells migrate, including the uveal tract. Uveal melanomas differ significantly from cutaneous melanoma in incidence, prognostic factors, molecular characteristics, and treatment. (Refer to the PDQ summary on Intraocular (Uveal) Melanoma Treatment for more information.)

Incidence and Mortality

Estimated new cases and deaths from melanoma in the United States in 2014:[1]

New cases: 76,100.

Deaths: 9,710.

Skin cancer is the most common malignancy diagnosed in the United States, with 3.5 million cancers diagnosed in 2 million people annually.[1] Melanoma represents less than 5% of skin cancers but results in most deaths.[1,2] The incidence has been increasing over the past four decades.[1] Elderly men are at highest risk; however, melanoma is the most common cancer in young adults aged 25 to 29 years and the second most common cancer in those aged 15 to 29 years.[3] Ocular melanoma is the most common cancer of the eye, with approximately 2,000 cases diagnosed annually.

Risk Factors

Risk factors for melanoma include both intrinsic (genetic and phenotype) and extrinsic (environmental or exposure) factors:

Anatomy

Schematic representation of normal skin. Melanocytes are also present in normal skin and serve as the source cell for melanoma. The relatively avascular epidermis houses both basal cell keratinocytes and squamous epithelial keratinocytes, the source cells for basal cell carcinoma and squamous cell carcinoma, respectively. The separation between epidermis and dermis occurs at the basement membrane zone, located just inferior to the basal cell keratinocytes.

Screening

Clinical Features

Melanoma occurs predominantly in adults, and more than 50% of the cases arise in apparently normal areas of the skin. Although melanoma can occur anywhere, including on mucosal surfaces and the uvea, melanoma in women occurs more commonly on the extremities, and in men it occurs most commonly on the trunk or head and neck.[4]

Early signs in a nevus that would suggest a malignant change include the following:

Darker or variable discoloration.

Itching.

An increase in size or the development of satellites.

Ulceration or bleeding (later signs).

Diagnosis

A biopsy, preferably by local excision, should be performed for any suspicious lesions. Suspicious lesions should never be shaved off or cauterized. The specimens should be examined by an experienced pathologist to allow for microstaging.

Studies show that distinguishing between benign pigmented lesions and early melanomas can be difficult, and even experienced dermatopathologists can have differing opinions. To reduce the possibility of misdiagnosis for an individual patient, a second review by an independent qualified pathologist should be considered.[5,6] Agreement between pathologists in the histologic diagnosis of melanomas and benign pigmented lesions has been studied and found to be considerably variable.[5,6]

Evidence (discordance in histologic evaluation):

One study found that there was discordance on the diagnosis of melanoma versus benign lesions in 37 of 140 cases examined by a panel of experienced dermatopathologists. For the histologic classification of cutaneous melanoma, the highest concordance was attained for Breslow thickness and presence of ulceration, while the agreement was poor for other histologic features such as Clark level of invasion, presence of regression, and lymphocytic infiltration.[5]

In another study, 38% of cases examined by a panel of expert pathologists had two or more discordant interpretations.[6]

Prognostic Factors

Prognosis is affected by the characteristics of primary and metastatic tumors. The most important prognostic factors have been incorporated into the revised 2009 American Joint Committee on Cancer staging and include the following:[4,7-9]

Thickness and/or level of invasion of the melanoma.

Mitotic index, defined as mitoses per millimeter.

Ulceration or bleeding at the primary site.

Number of regional lymph nodes involved, with distinction of macrometastasis and micrometastasis.

Systemic metastasis.

Site—nonvisceral versus lung versus all other visceral sites.

Elevated serum lactate dehydrogenase level.

Patients who are younger, who are female, and who have melanomas on their extremities generally have better prognoses.[4,7-9]

Microscopic satellites, recorded as present or absent, in stage I melanoma may be a poor prognostic histologic factor, but this is controversial.[10] The presence of tumor infiltrating lymphocytes, which may be categorized as brisk, nonbrisk, or absent, is under study as a potential prognostic factor.[11]

The risk of relapse decreases substantially over time, although late relapses are not uncommon.[12,13]

Related Summaries

Other PDQ summaries containing information related to melanoma include the following:

Cellular and Molecular Classification of Melanoma

The descriptive terms for clinicopathologic cellular subtypes of malignant melanoma should be considered of historic interest only; they do not have independent prognostic or therapeutic significance. The cellular subtypes are the following:

Superficial spreading.

Nodular.

Lentigo maligna.

Acral lentiginous (palmar/plantar and subungual).

Miscellaneous unusual types:

Mucosal lentiginous (oral and genital).

Desmoplastic.

Verrucous.

Identification of activating mutations in the mitogen-activated protein (MAP) kinase pathway served as a catalyst to develop a molecular classification of melanoma. Such a classification provides potential drug targets, directions for future clinical trials, and the ability to select patients for targeted therapies.

BRAF gene mutations

BRAF (V-raf murine sarcoma viral oncogene homolog B1) genes, first reported in 2002, are the most frequent mutations in cutaneous melanoma. Approximately 40% to 60% of malignant melanomas harbor a single nucleotide transversion in BRAF. Most have a mutation that results in a substitution from valine to glutamic acid at position 600 (BRAF V600E); less frequent mutations include valine 600 to lysine or arginine residues (V600K/R).[1]

Drugs that target this mutation by inhibiting BRAF are under evaluation in clinical trials. Vemurafenib was approved by the U.S. Food and Drug Administration (FDA) in 2011 for the treatment of unresectable or metastatic melanoma in patients who test positive for the BRAF mutation, as detected by an FDA-approved test (e.g., cobas 4800 BRAF V600 Mutation Test).

Other gene mutations

In smaller subsets of cutaneous melanoma, other activating mutations have been described, including the following:

c-KIT: A c-KIT mutation, or increased copy number, is associated with mucosal and acral melanomas (which comprise 6%–7% of melanomas in whites but are the most common subtype in the Asian population).[4-6]

CDK4 (cyclin-dependent kinase 4): CDK4 mutations have been described in approximately 4% of melanomas and are also more common in acral and mucosal melanomas.[7,8]

Drugs developed to target these mutations are currently in clinical trials.

Uveal melanomas differ significantly from cutaneous melanomas; in one series, 83% of 186 uveal melanomas were found to have a constitutively active somatic mutation in GNAQ or GNA11.[9,10] (Refer to the PDQ summary on Intraocular (Uveal) Melanoma Treatment for more information.)

Stage Information for Melanoma

Clinical staging is based on whether the tumor has spread to regional lymph nodes or distant sites. For melanoma that is clinically confined to the primary site, the chance of lymph node or systemic metastases increases as the thickness and depth of local invasion increases, which worsens the prognosis. Melanoma can spread by local extension (through lymphatics) and/or by hematogenous routes to distant sites. Any organ may be involved by metastases, but lungs and liver are common sites.

The microstage of malignant melanoma is determined on histologic examination by the vertical thickness of the lesion in millimeters (Breslow classification) and/or the anatomic level of local invasion (Clark classification). The Breslow thickness is more reproducible and more accurately predicts subsequent behavior of malignant melanoma in lesions thicker than 1.5 mm and should always be reported.

Accurate microstaging of the primary tumor requires careful histologic evaluation of the entire specimen by an experienced pathologist.

Clark Classification (Level of Invasion)

Table 1. Clark Classification (Level of Invasion)

Level of Invasion

Description

Level I

Lesions involving only the epidermis (in situ melanoma); not an invasive lesion.

Level II

Invasion of the papillary dermis; does not reach the papillary-reticular dermal interface.

Level III

Invasion fills and expands the papillary dermis but does not penetrate the reticular dermis.

Level IV

Invasion into the reticular dermis but not into the subcutaneous tissue.

aClinical staging includes microstaging of the primary melanoma and clinical and/or radiologic evaluation for metastases. By convention, it should be used after complete excision of the primary melanoma with clinical assessment for regional and distant metastases.

bPathologic staging includes microstaging of the primary melanoma and pathologic information about the regional lymph nodes after partial or complete lymphadenectomy. Pathologic stage 0 or stage IA patients are the exception; they do not require pathologic evaluation of their lymph nodes.

Treatment Option Overview for Melanoma

aClinical trials are an important option for patients with all stages of melanoma because advances in understanding the aberrant molecular and biologic pathways have led to rapid drug development. Standard treatment options are available in many clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

Excision

Surgical excision remains the primary modality for treating melanoma. Cutaneous melanomas that have not spread beyond the site at which they developed are highly curable. The treatment for localized melanoma is surgical excision with margins proportional to the microstage of the primary lesion.

Lymph node management

Sentinel lymph node biopsy (SLNB)

Lymphatic mapping and SLNB can be considered to assess the presence of occult metastasis in the regional lymph nodes of patients with primary tumors larger than 1 to 4 mm, potentially identifying individuals who may be spared the morbidity of regional lymph node dissections (LNDs) and individuals who may benefit from adjuvant therapy.[1-6]

To ensure accurate identification of the sentinel lymph node (SLN), lymphatic mapping and removal of the SLN should precede wide excision of the primary melanoma.

Multiple studies have demonstrated the diagnostic accuracy of SLNB, with false-negative rates of 0% to 2%.[1,6-11] If metastatic melanoma is detected, a complete regional lymphadenectomy can be performed in a second procedure.

Complete lymph node dissection (CLND)

Patients can be considered for CLND if the sentinel node(s) is microscopically or macroscopically positive for regional control or considered for entry into the Multicenter Selective Lymphadenectomy Trial II (NCT00297895) to determine whether CLND affects survival. SLNB should be performed prior to wide excision of the primary melanoma to ensure accurate lymphatic mapping.

Adjuvant Therapy

High-dose interferon alpha-2b was approved by the U.S. Food and Drug Administration (FDA) in 1995 for the adjuvant treatment of patients with melanoma who have undergone a complete surgical resection but who are considered to be at a high risk of relapse (stages IIB, IIC, and III). However, prospective, randomized, multicenter treatment trials have demonstrated that high-dose interferon alpha-2b and pegylated interferon improve relapse-free survival but do not improve overall survival (OS).

Therapies that have improved OS in patients with recurrent or metastatic disease are now being tested as adjuvant therapy in clinical trials, including NCT01274338, NCT01667419, and NCT01682083.

Limb Perfusion

A completed, multicenter, phase III randomized trial (SWOG-8593) of patients with high-risk primary stage I limb melanoma did not show a disease-free survival or OS benefit from isolated limb perfusion with melphalan, when compared with surgery alone.[5]

Although melanoma that has spread to distant sites is rarely curable, treatment options are rapidly expanding. Two approaches—checkpoint inhibition and targeting the mitogen-activated protein kinase pathway—have demonstrated improvement in OS in randomized trials in comparison to dacarbazine (DTIC). Although none appear to be curative when used as single agents, early data of combinations are promising. Given the rapid development of new agents and combinations, patients and their physicians are encouraged to consider treatment in a clinical trial for initial treatment and at the time of progression.

Immunotherapy

Checkpoint inhibitors: Ipilimumab has demonstrated an improvement in progression-free survival (PFS) and OS in international, multicenter, randomized trials in patients with unresectable or advanced disease, resulting in FDA approval in 2011. In an international, multicenter, randomized trial, pembrolizumab received accelerated approval in 2014 for demonstrating durable responses in patients whose disease had progressed after they received ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Multiple phase III trials of PD-1 (programmed cell death-1) and PD-L1 (programmed death-ligand 1) checkpoint inhibitors alone and in combination (e.g., with ipilimumab) are in progress to assess their ability to improve PFS and OS.

Interleukin-2 (IL-2): IL-2 was approved by the FDA in 1998 on the basis of durable complete response (CR) rates in a minority of patients (6%–7%) with previously treated metastatic melanoma in eight phase I and II studies. Phase III trials comparing high-dose IL-2 with other treatments and providing an assessment of relative impact on OS have not been conducted.

Signal transduction inhibitors

Studies to date indicate that both BRAF and MEK inhibitors can significantly impact the natural history of melanoma, although they do not appear to be curative as single agents.

BRAF inhibitors

Vemurafenib

Vemurafenib, approved by the FDA in 2011, has demonstrated an improvement in PFS and OS in patients with unresectable or advanced disease. Vemurafenib is an orally available, small-molecule, selective BRAF V600E kinase inhibitor, and its indication is limited to patients with a demonstrated BRAF V600E mutation by an FDA-approved test.[11]

Dabrafenib

Dabrafenib, an orally available, small-molecule, selective BRAF inhibitor that was approved by the FDA in 2013, showed improvement in PFS when compared with DTIC in an international, multicenter trial (BREAK-3 [NCT01227889]).

MEK inhibitors

Trametinib

Trametinib is an orally available, small-molecule, selective inhibitor of MEK1 and MEK2 that was approved by the FDA in 2013 for patients with unresectable or metastatic melanoma with BRAF V600E or K mutations. Trametinib demonstrated improved PFS over DTIC.

Combination signal transduction therapy

In 2014, the combination of dabrafenib and trametinib received accelerated approval from the FDA for patients with unresectable or metastatic melanomas that carry the BRAF V600E or V600 K mutation. The combination demonstrated improved durable response rates over single-agent dabrafenib. Full approval is pending completion of ongoing clinical trials and demonstration of clinical benefit on OS.

c-KIT inhibitors

Early data suggest that mucosal or acral melanomas with activating mutations or amplifications in c-KIT may be sensitive to a variety of c-KIT inhibitors.[12-14] Phase II and phase III trials are available for patients with unresectable stage III or stage IV melanoma harboring the c-KIT mutation.

Chemotherapy

DTIC: DTIC was approved in 1970 on the basis of overall response rates. Phase III trials indicate an overall response rate of 10% to 20%, with rare CRs observed. An impact on OS has not been demonstrated in randomized trials.[15-18] When used as a control arm for recent registration trials of ipilimumab and vemurafenib in previously untreated patients with metastatic melanoma, DTIC was shown to be inferior for OS.

Temozolomide: Temozolomide, an oral alkylating agent, appeared to be similar to intravenous DTIC in a randomized phase III trial with a primary endpoint of OS; however, because the trial was designed to demonstrate the superiority of temozolomide, which was not achieved, the trial was left with a sample size that was inadequate to provide statistical proof of noninferiority.[16]

Palliative local therapy

Melanoma metastatic to distant, lymph node–bearing areas may be palliated by regional lymphadenectomy. Isolated metastases to the lung, gastrointestinal tract, bone, or sometimes the brain may be palliated by resection, with occasional long-term survival.[19-21]

Stage 0 Melanoma Treatment

Standard Treatment Options for Stage 0 Melanoma

Excision

Patients with stage 0 disease may be treated by excision with minimal, but microscopically free, margins.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage 0 melanoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

A multicenter, phase III randomized trial (SWOG-8593) of patients with high-risk stage I primary limb melanoma did not show a DFS or OS benefit from isolated limb perfusion with melphalan, when compared with surgery alone.[6,7]

Lymph node management

Elective regional lymph node dissection is of no proven benefit for patients with stage I melanoma.[8]

Lymphatic mapping and sentinel lymph node biopsy (SLNB) for patients who have tumors of intermediate thickness and/or ulcerated tumors may identify individuals with occult nodal disease. These patients may benefit from regional lymphadenectomy and adjuvant therapy.[6,9-11]

The International Multicenter Selective Lymphadenectomy Trial (MSLT-1 [JWCI-MORD-MSLT-1193]) included 1,269 patients with intermediate-thickness (defined as 1.2 mm–3.5 mm in this study) primary melanomas.[12][Level of evidence: 1iiB]

There was no melanoma-specific survival advantage (primary endpoint) for patients randomly assigned to undergo wide excision plus SLNB, followed by immediate complete lymphadenectomy for node positivity versus nodal observation and delayed lymphadenectomy for subsequent nodal recurrence at a median of 59.8 months.

This trial was not designed to detect a difference in the impact of lymphadenectomy in patients with microscopic lymph node involvement.

The Sunbelt Melanoma Trial (UAB-9735 [NCT00004196]) was a phase III trial to determine the effects of lymphadenectomy with or without adjuvant high-dose interferon alpha-2b versus observation on DFS and OS in patients with submicroscopic sentinel lymph node (SLN) metastasis detected only by the polymerase chain reaction assay (i.e., SLN negative by histology and immunohistochemistry).

No survival data have been reported from this study.

Treatment Options Under Clinical Evaluation for Stage I Melanoma

Treatment options under clinical evaluation for patients with stage I melanoma include the following:

Clinical trials evaluating new techniques to detect submicroscopic SLN metastasis. Because of the higher rate of treatment failure in the subset of clinical stage I patients with occult nodal disease, clinical trials have evaluated new techniques to detect submicroscopic SLN metastasis to identify patients who may benefit from regional lymphadenectomy with or without adjuvant therapy.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I melanoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

This study suggests that 1-cm margins may not be adequate for patients with melanomas thicker than 2 mm.

Lymph Node Management

Lymphatic mapping and sentinel lymph node biopsy (SLNB)

Lymphatic mapping and SLNB have been used to assess the presence of occult metastasis in the regional lymph nodes of patients with stage II disease, potentially identifying individuals who may be spared the morbidity of regional lymph node dissections (LNDs) and individuals who may benefit from adjuvant therapy.[3-7]

To ensure accurate identification of the sentinel lymph node (SLN), lymphatic mapping and removal of the SLN should precede wide excision of the primary melanoma.

With the use of a vital blue dye and a radiopharmaceutical agent injected at the site of the primary tumor, the first lymph node in the lymphatic basin that drains the lesion can be identified, removed, and examined microscopically. Multiple studies have demonstrated the diagnostic accuracy of SLNB, with false-negative rates of 0% to 2%.[3,8-12] If metastatic melanoma is detected, a complete regional lymphadenectomy can be performed in a second procedure.

Regional lymphadenectomy

No published data on the clinical significance of micrometastatic melanoma in regional lymph nodes are available from prospective trials. Some evidence suggests that for patients with tumors of intermediate thickness and occult metastasis, survival is better among patients who undergo immediate regional lymphadenectomy than it is among those who delay lymphadenectomy until the clinical appearance of nodal metastasis.[13] This finding should be viewed with caution because it arose from a post hoc subset analysis of data from a randomized trial.

Evidence (regional lymphadenectomy):

The International Multicenter Selective Lymphadenectomy Trial (MSLT-1 [JWCI-MORD-MSLT-1193]) included 1,269 patients with intermediate-thickness (defined as 1.2 mm–3.5 mm in this study) primary melanomas.[14][Level of evidence: 1iiB]

There was no melanoma-specific survival advantage (primary endpoint) for patients randomly assigned to undergo wide excision plus SLNB, followed by immediate complete lymphadenectomy for node positivity versus nodal observation and delayed lymphadenectomy for subsequent nodal recurrence at a median of 59.8 months.

This trial was not designed to detect a difference in the impact of lymphadenectomy in patients with microscopic lymph node involvement.

Three other prospective randomized trials have failed to show a survival benefit for prophylactic regional LNDs.[15-17]

Adjuvant therapy

High-dose interferon

High-dose interferon alpha-2b was approved in 1995 for the adjuvant treatment of patients with melanoma who have undergone a complete surgical resection but are considered to be at a high risk of relapse. Evidence was based on a significantly improved relapse-free survival (RFS) and marginally improved overall survival (OS) that were seen in EST-1684.

Subsequent large, randomized trials have not been able to reproduce a benefit in OS. Ongoing trials are testing therapies that have demonstrated improved OS in patients with stage IV disease.

Clinicians should be aware that the high-dose regimens have significant toxic effects.

Evidence (high-dose interferon alpha-2b):

A multicenter, randomized, controlled study (EST-1684) compared a high-dose regimen of interferon alpha-2b (20 mU/m2 of body surface per day given intravenously 5 days a week for 4 weeks, then 10 mU/m2 of body surface per day given subcutaneously 3 times a week for 48 weeks) with observation.[8][Level of evidence: 1iiA]

This study included 287 patients at high risk of recurrence after potentially curative surgery for melanoma (patients with melanomas thicker than 4 mm without involved lymph nodes or patients with melanomas of any thickness with positive lymph nodes).

Patients who had recurrent melanoma involving only the regional lymph nodes were also eligible.

At a median follow-up of 7 years, this trial demonstrated a significant prolongation of RFS (P = .002) and OS (P = .024) for patients who received high-dose interferon.

The median OS for patients who received the high-dose regimen of interferon alpha-2b was 3.8 years, compared with 2.8 years for those in the observation group.

A subset analysis of the stage II patients failed to show any RFS or OS benefit from high-dose interferon. Because the number of stage II patients was small in this subset analysis, it is difficult to draw meaningful conclusions from this study for this specific group.

A multicenter, randomized, controlled study (EST-1690) conducted by the same investigators compared the same high-dose interferon alpha regimen with either a low-dose regimen of interferon alpha-2b (3 mU/m2 of body surface per day given subcutaneously 3 times per week for 104 weeks) or observation. The stage entry criteria for this trial included patients with stage II and III melanoma. This three-arm trial enrolled 642 patients.[9][Level of evidence: 1iiA]

At a median follow-up of 52 months, a statistically significant RFS advantage was shown for all patients who received high-dose interferon (including the clinical stage II patients) when compared with the observation group (P = .03).

No statistically significant RFS advantage was seen for patients who received low-dose interferon when compared with the observation group.

The 5-year estimated RFS rate was 44% for the high-dose interferon group, 40% for the low-dose interferon group, and 35% for the observation group.

Treatment Options Under Clinical Evaluation for Stage II Melanoma

Postsurgical adjuvant treatment (e.g., with interferons) has not been shown to affect survival.

Treatment options under clinical evaluation for patients with stage II melanoma include the following:

Clinical trials are testing therapies of postsurgical adjuvant treatment that have improved OS in patients with stage IV disease, including NCT01274338, NCT01667419, and NCT01682083. Postsurgical adjuvant treatment (e.g., with interferons) has not been shown to affect survival; therefore, clinical trials are an important therapeutic option for patients at high risk for relapse.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage II melanoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Resectable Stage III Melanoma Treatment

Standard Treatment Options for Resectable Stage III Melanoma

Excision

The primary tumor may be treated with wide local excision with 1-cm to 3-cm margins, depending on tumor thickness and location.[1-7] Skin grafting may be necessary to close the resulting defect.

Lymph node management

Sentinel lymph node biopsy (SLNB)

Lymphatic mapping and SLNB can be considered to assess the presence of occult metastases in the regional lymph nodes of patients with primary tumors larger than 1 mm to 4 mm, potentially identifying individuals who may be spared the morbidity of regional lymph node dissections (LNDs) and individuals who may benefit from adjuvant therapy.[3,8-12]

To ensure accurate identification of the sentinel lymph node (SNL), lymphatic mapping and removal of the SLN should precede wide excision of the primary melanoma.

Multiple studies have demonstrated the diagnostic accuracy of SLNB, with false-negative rates of 0% to 2%.[8,12-17] If metastatic melanoma is detected, a complete regional lymphadenectomy can be performed in a second procedure.

Complete lymph node dissection (CLND)

Patients can be considered for CLND if the sentinel node(s) is microscopically or macroscopically positive for regional control or considered for entry into the Multicenter Selective Lymphadenectomy Trial II to determine whether CLND affects survival. SLNB should be performed prior to wide excision of the primary melanoma to ensure accurate lymphatic mapping.

Adjuvant Therapy

Interferon alpha-2b

Prospective, randomized, multicenter treatment trials have demonstrated that high-dose interferon alpha-2b and pegylated interferon, both approved for the adjuvant treatment of patients at high risk for relapse, can improve relapse-free survival (RFS) but do not improve overall survival (OS). Agents that have demonstrated improved OS in patients with recurrent or metastatic disease are now being tested in clinical trials of adjuvant therapy in patients at high risk for relapse after surgical resection of tumor. These trials include NCT01274338, NCT01667419, and NCT01682083.

Evidence (high-dose alpha interferon):

A multicenter, randomized, controlled study (EST-1690) compared a high-dose interferon alpha regimen with either a low-dose regimen of interferon alpha-2b (3 mU/m2 of body surface per day given subcutaneously three times per week for 104 weeks) or observation. The stage entry criteria for this trial included patients with stage II and III melanoma. This three-arm trial enrolled 642 patients.[14][Level of evidence: 1iiA]

At a median follow-up of 52 months, a statistically significant RFS advantage was shown for all patients who received high-dose interferon (including the clinical stage II patients) when compared with the observation group (P = .03).

No statistically significant RFS advantage was seen for patients who received low-dose interferon when compared with the observation group.

The 5-year estimated RFS rate was 44% for the high-dose interferon group, 40% for the low-dose interferon group, and 35% for the observation group.

Pooled analyses (EST-1684 and EST-1690) of the high-dose arms versus the observation arms suggest that treatment confers a significant RFS advantage but not a significant benefit for survival.

A randomized, multicenter, national trial, ECOG-1697 [NCT00003641], evaluated high-dose intravenous interferon for a short duration (1 month) versus observation in patients with node-negative melanoma at least 2 mm thick or with any thickness and positive sentinel nodes. This trial was closed at interim analysis because of the lack of benefit from treatment with interferon.

Pegylated interferon alpha-2b

In 2011, pegylated interferon alpha-2b, which is characterized by a longer half-life and can be administered subcutaneously, was approved by the U.S. Food and Drug Administration for the adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of complete surgical resection, including complete lymphadenectomy.

Evidence (pegylated interferon alpha-2b):

Approval of pegylated interferon alpha-2b was based on EORTC-18991 [NCT00006249], which randomly assigned 1,256 patients with resected stage III melanoma to observation or weekly subcutaneous pegylated interferon alpha-2b for up to 5 years.[15][Level of evidence: 1iiDii]

Treatment options under clinical evaluation for patients with resectable stage III melanoma include the following:

Adjuvant therapy that can impact OS.

Intralesional therapies.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III melanoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Although melanoma that has spread to distant sites is rarely curable, treatment options are rapidly expanding. Two approaches—checkpoint inhibition and targeting the mitogen-activated protein kinase (MAPK) pathway—have demonstrated improvement in overall survival (OS) in randomized trials versus the use of dacarbazine (DTIC) or in comparison to DTIC. Although none appear to be curative when used as single agents, early data of combinations are promising. Given the rapid development of new agents and combinations, patients and their physicians are encouraged to consider treatment in a clinical trial for initial treatment and at the time of progression.

Immunotherapy

Checkpoint inhibitors

Anti–CTLA-4: ipilimumab

Ipilimumab is a human monoclonal antibody that binds to CTLA-4, thereby blocking its ability to down-regulate T-cell activation, proliferation, and effector function.

Ipilimumab has demonstrated clinical benefit by prolonging OS in randomized trials, and was approved by the U.S. Food and Drug Administration (FDA) in 2011. Two prospective, randomized, international trials, one each in previously untreated and treated patients, supported the use of ipilimumab.[1,2]

Evidence (ipilimumab):

Previously treated patients: A total of 676 patients with previously treated, unresectable stage III or stage IV disease, and who were HLA-A*0201 positive, were entered into a three-arm, multinational, randomized (3:1:1), double-blind, double-dummy trial. A total of 403 patients were randomly assigned to receive ipilimumab (3 mg/kg every 3 weeks for 4 doses) with glycoprotein 100 (gp100) peptide vaccine. One hundred thirty-seven patients received ipilimumab (3 mg/kg every 3 weeks for 4 doses), and 136 patients received the gp100 vaccine. Patients were stratified by baseline metastases and previous receipt or nonreceipt of interleukin-2 (IL-2) therapy. Eighty-two of the patients had metastases to the brain at baseline.[2][Level of evidence: 1iA]

An analysis at 1 year showed that among patients treated with ipilimumab, 44% of those treated with ipilimumab and 45% of those treated with ipilimumab and the vaccine were alive, compared with 25% of the patients who received the vaccine only.

Grade 3 or grade 4 immune-related adverse events (irAEs) occurred in 10% to 15% of patients treated with ipilimumab. These irAEs most often included diarrhea or colitis, and endocrine-related events (e.g., inflammation of the pituitary). These events required cessation of therapy and institution of anti-inflammatory agents such as corticosteroids or, in four cases, infliximab (an antitumor necrosis factor-alpha antibody).

There were 14 drug-related deaths (2.1%), and seven deaths were associated with irAEs.

Previously untreated patients: A multicenter, international trial randomly assigned 502 patients untreated for metastatic disease (adjuvant treatment was allowed) in a 1:1 ratio to receive ipilimumab (10 mg/kg) plus DTIC (850 mg/m2) or placebo plus DTIC (850 mg/m2) at weeks 1, 4, 7, and 10 followed by DTIC alone every 3 weeks through week 22. Patients with stable disease or an objective response and no dose-limiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary endpoint was survival. Patients were stratified according to Eastern Cooperative Oncology Group (ECOG) performance status (PS) and metastatic stage. Approximately 70% of the patients had an ECOG PS of 0, and the remainder of the patients had an ECOG PS of 1. Approximately 55% of patients had stage M1c disease.[1][Level of evidence: 1iA]

The median OS was 11.2 months (95% confidence interval [CI], 9.4–13.6) for the ipilimumab-DTIC group, versus 9.1 months (95% CI, 7.8–10.5) for the placebo-DTIC group. Estimated survival rates in the ipilimumab-DTIC group were 47.3% at 1 year, 28.5% at 2 years, and 20.8% at 3 years (HR for death, 0.72; P < .001); and in the placebo-DTIC group, the rates were 36.3% at 1 year, 17.9% at 2 years, and 12.2% at 3 years.

The most common study-drug–related adverse events (AEs) were those classified as immune related. Grade 3 or grade 4 irAEs were seen in 38.1% of patients treated with ipilimumab plus DTIC versus 4.4% of patients treated with placebo plus DTIC, the most common events were hepatitis and enterocolitis.

No drug-related deaths occurred.

Clinicians and patients should be aware that immune-mediated adverse reactions may be severe or fatal. Early identification and treatment, including potential administration of systemic glucocorticoids or other immunosuppressants according to the immune-mediated adverse reaction management guide provided by the manufacturer, are necessary.[3]

Anti–PD-1 and PD-L1

The PD-1 pathway is a key immunoinhibitory mediator of T-cell exhaustion. Blockade of this pathway can lead to T-cell activation, expansion, and enhanced effector functions. PD-1 has 2 ligands, PD-L1 and PD-L2 (Programmed Death-2 Ligand 2).

Pembrolizumab

Pembrolizumab was granted accelerated approval by the FDA in September 2014 for patients with unresectable or metastatic melanoma who have progressed despite therapy with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Pembrolizumab is a human monoclonal antibody that binds to the PD-1 receptor, preventing it from binding to its ligands, PD-L1 and PD-L2. The FDA granted accelerated approval based on the surrogate endpoint of durable response rate in an international, multicenter, open-label, randomized, dose-comparative trial. As a condition to accelerated approval, randomized trials to assess clinical benefit, e.g., improvement in progression-free survival (PFS) and OS versus standard therapy, is required.

Evidence (pembrolizumab):

Previously treated patients. A total of 173 patients with unresectable or metastatic melanoma with disease progression within 24 weeks of the last dose of ipilimumab and, if BRAF V600 mutation positive, previous treatment with a BRAF inhibitor, were randomly assigned to one of two doses of pembrolizumab—2 mg/kg or 10 mg/kg—every 3 weeks. The trial excluded patients with an autoimmune disease, a condition requiring immunosuppression, or a history of severe irAEs from treatment with ipilimumab.

The median age was 61 years; 60% were male; 67% had an ECOG PS of 0, and 33% had an ECOG PS of 1. Eighteen percent of patients had tumors that were BRAF V600 mutation positive, 39% had an elevated lactate dehydrogenase (LDH), 64% had M1c disease, 9% had brain metastases, and 72% had undergone two or more therapies for advanced disease. The primary outcome measure was overall response rate (ORR) according to Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) criteria as assessed by blinded independent central review.[4][Level of evidence: 1iiDiv]

The ORR determined by independent central review was 26% (95% CI, -14–13; P = .96) in the 2 mg/kg arm, consisting of one complete response (CR) and 20 partial responses (PRs) in 81 patients. Median follow-up was 8 months, and all patients had a minimum of 6 months of follow-up. Among the 21 patients with an objective response, 18 had ongoing responses, ranging from 1.4+ months to 8.5+ months.

Response rate in the 10 mg/kg arm was similar at 26%, consisting of 20 responses in 76 patients. Responses were seen in patients with and without BRAF V600 mutations.

The approved dose was 2 mg/kg administered as an intravenous (IV) infusion for 30 minutes every 3 weeks.

Pembrolizumab was discontinued because of AEs in 7% of the patients treated with 2 mg/kg, with 3% considered drug-related AEs by the investigators. The most common AEs in the 2 mg/kg versus 10 mg/kg arms were:

Fatigue (33% vs. 37%).

Pruritus (23% vs. 19%).

Rash (18% vs. 18%).

Other common AEs included cough, nausea, decreased appetite, constipation, arthralgia, and diarrhea. The most frequent and serious AEs that occurred in more than 2% of a total of 411 patients treated with pembrolizumab included renal failure, dyspnea, pneumonia, and cellulitis. Additional clinically significant irAEs included pneumonitis, colitis, hypophysitis, hyperthyroidism, hypothyroidism, nephritis, and hepatitis.

High-dose interleukin-2 (IL-2)

IL-2 was approved by the FDA in 1998 on the basis of durable CRs in eight phase I and II studies. Phase III trials comparing high-dose IL-2 to other retreatments, providing an assessment of relative impact on OS, have not been conducted.

Evidence (high-dose IL-2):

Based on a pooled analysis of 270 patients from eight single- and multi-institutional trials in 22 institutions conducted between 1985 and 1993:

With a median follow-up time for surviving patients of at least 7 years, the median duration of CRs was not reached but was at least 59 months.[6]

Strategies to improve this therapy are an active area of investigation.

Dual immunomodulation

T-cells coexpress several receptors that inhibit T-cell function. Preclinical data and early clinical data suggest that coblockade of the two inhibitory receptors, CTLA-4 and PD-1, may be more effective than blockade of either alone. This has led to a phase III trial comparing each single agent to the combination (NCT01844505).

Signal transduction inhibitors

Studies to date indicate that both BRAF and MEK (mitogen-activated ERK-[extracellular signal-regulated kinase] activating kinase) inhibitors, as single agents and in combination, can significantly impact the natural history of melanoma, although they do not appear to provide a cure.

BRAF inhibitors

Vemurafenib

Vemurafenib is an orally available, small molecule, selective BRAF kinase inhibitor that was approved by the FDA in 2011 for patients with unresectable or metastatic melanoma who test positive for the BRAF V600E mutation.

Treatment with vemurafenib is discouraged in wild-type BRAF melanoma because data from preclinical models have demonstrated that BRAF inhibitors can enhance rather than down-regulate the MAPK pathway in tumor cells with wild-type BRAF and upstream RAS mutations.[7-10]

Evidence (vemurafenib):

Previously untreated patients: The approval of vemurafenib was supported by an international, multicenter trial (BRIM-3 [NCT01006980]) that screened 2,107 patients with previously untreated stage IIIC or IV melanoma for the BRAF V600 mutation and identified 675 patients via the cobas 4800 BRAF V600 Mutation Test.[11] Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or DTIC (1,000 mg/m2 IV every 3 weeks). Coprimary endpoints were rates of OS and PFS. At the planned interim analysis, the Data and Safety Monitoring Board determined that both the OS and PFS endpoints had met the prespecified criteria for statistical significance in favor of vemurafenib and recommended that patients in the DTIC group be allowed to cross over to receive vemurafenib.[11][Levels of evidence: 1iiA and 1iiDiii]

A total of 675 patients were evaluated for OS; although the median survival had not yet been reached for vemurafenib and the data were immature for reliable Kaplan-Meier estimates of survival curves, the OS in the vemurafenib arm was clearly superior to that in the DTIC arm.

The HR for death in the vemurafenib group was 0.37 (95% CI, 0.26–0.55; P < .001). The survival benefit in the vemurafenib group was observed in each prespecified subgroup, for example, age, sex, ECOG PS, tumor stage, lactic dehydrogenase, and geographic region.

The HR for tumor progression in the vemurafenib arm was 0.26 (95% CI, 0.20–0.33; P < .001). The estimated median PFS was 5.3 months in the vemurafenib arm versus 1.6 months in the DTIC arm.

Twenty patients had non-BRAF V600E mutations: 19 with BRAF V600K and 1 with BRAF V600D. Four patients with a BRAF V600K mutation had a response to vemurafenib.

AEs required dose modification or interruption in 38% of patients receiving vemurafenib and 16% of those receiving DTIC. The most common AEs with vemurafenib were cutaneous events (i.e., arthralgia and fatigue). Cutaneous squamous cell carcinoma (SCC), keratoacanthoma, or both developed in 18% of patients and were treated by simple excision. The most common AEs with DTIC were fatigue, nausea, vomiting, and neutropenia. (Refer to the PDQ summaries on Supportive and Palliative Care for more information on coping with cancer.)

Previously treated patients: A total of 132 patients with a BRAF V600E or BRAF V600K mutation were enrolled in a multicenter phase II trial of vemurafenib, which was administered as 960 mg orally twice daily. Of the enrolled patients, 61% had stage M1c disease, and 49% had an elevated LDH level. All patients had received one or more prior therapies for advanced disease. Median follow-up was 12.9 months.[12][Level of evidence: 3iiiDiv]

Median duration of response per IRC assessment was 6.7 months (95% CI, 5.6–8.6). Most responses were evident at the first radiologic assessment at 6 weeks; however, some patients did not respond until after receiving therapy for more than 6 months.

Dabrafenib

Dabrafenib is an orally available, small molecule, selective BRAF inhibitor that was approved by the FDA in 2013 for patients with unresectable or metastatic melanoma who test positive for the BRAF V600E mutation as detected by an FDA-approved test. Dabrafenib and other BRAF inhibitors are not recommended for treatment of BRAF wild type melanomas, as in vitro experiments suggest there may be a paradoxical stimulation of MAPK signaling resulting in tumor promotion.

Evidence (dabrafenib):

An international, multicenter trial (BREAK-3 [NCT01227889]) compared dabrafenib with DTIC. A total of 250 patients with unresectable stage III or IV melanoma and BRAF V600E mutations were randomly assigned in a 3:1 ratio (dabrafenib 150 mg orally twice a day or DTIC 1,000 mg/m2 IV every 3 weeks). IL-2 was allowed as prior treatment for advanced disease. The primary endpoint was PFS; patients could cross over at the time of progressive disease after confirmation by a blinded IRC.[13][Level of Evidence: 1iiDiii]

The most frequent AEs in patients treated with dabrafenib were cutaneous findings (i.e., hyperkeratosis, papillomas, palmar-plantar erythrodysesthesia), pyrexia, fatigue, headache, and arthralgia. Cutaneous SCC or keratoacanthoma occurred in 12 patients, basal cell carcinoma occurred in four patients, mycosis fungoides occurred in one patient, and new melanoma occurred in two patients.

In 2013, trametinib was approved by the FDA for patients with unresectable or metastatic melanoma with BRAF V600E or K mutations, as determined by an FDA-approved test.

Evidence (trametinib):

A total of 1,022 patients were screened for BRAF mutations, resulting in 322 eligible patients (281 with BRAF V600E, 40 with BRAF V600K, and one with both mutations).[14] One previous treatment (biologic or chemotherapy) was allowed; however, no previous treatment with a BRAF or MEK inhibitor was permitted. Patients were randomly assigned in a 2:1 ratio to receive trametinib (2 mg once daily) or IV chemotherapy (either DTIC 1,000 mg/m2 every 3 weeks or paclitaxel 175 mg/m2 every 3 weeks). Crossover for patients randomly assigned to chemotherapy was allowed; therefore, the primary endpoint was PFS.

The investigator-assessed PFS was 4.8 months in patients receiving trametinib versus 1.5 months in the chemotherapy group (HR for PFS or death, 0.45; 95% CI, 0.33–0.63; P < .001). A radiology review blinded-to-treatment arm resulted in similar outcomes. Median OS has not been reached.

AEs leading to dose interruptions occurred in 35% of patients in the trametinib group and 22% of those in the chemotherapy group. AEs leading to dose reductions occurred in 27% of patients receiving trametinib and in 10% of those receiving chemotherapy.

The most common AEs included rash, diarrhea, nausea, vomiting, fatigue, peripheral edema, alopecia, hypertension, and constipation. Cardiomyopathy (7%), interstitial lung disease (2.4%), central serous retinopathy (<1%), and retinal-vein occlusion (<1%) are uncommon but serious AEs associated with trametinib. On-study cutaneous SCCs were not observed. (Refer to the PDQ summaries on Supportive and Palliative Care for more information on coping with cancer.)

Combination therapy with signal transduction inhibitors

Resistance to BRAF inhibitors, in patients with BRAF V600 mutations, may be associated with reactivation of the MAPK pathway. Combinations of signal transduction inhibitors that block different sites in the same pathway or sites in multiple pathways are an active area of research.

Evidence (combination therapy with signal transduction inhibitors):

In January 2014, the FDA granted accelerated approval to dabrafenib and trametinib in combination to treat patients with unresectable or metastatic melanomas who carry the BRAF V600E or V600K mutation as detected by an FDA-approved test. Accelerated approval was granted on the basis of objective response rates from an open-label phase II trial that randomly assigned 162 patients with unresectable or metastatic melanoma with the BRAF V600E or V600K mutation in a 1:1:1 ratio to receive dabrafenib alone (150 mg twice a day) or with trametinib (at a dose of either 1 mg or 2 mg twice a day).[15] Patients who had disease progression on dabrafenib monotherapy could cross over to receive the combination of dabrafenib 150 mg plus trametinib 2 mg twice a day. Patients were allowed to have received one previous therapy other than a BRAF or MEK inhibitor.[15][Level of evidence: 1iiDiv].

Patients treated with the combination had a response rate of 76%, with an average duration of 10.5 months. Patients treated with dabrafenib alone had a response rate of 54%, with an average duration of 5.6 months.

The development of a new SCC of the skin associated with single-agent dabrafenib was reduced in the combination arm (19% with dabrafenib and 7% with the combination).

The most frequent AEs in the combination were pyrexia and chills, fatigue, nausea, vomiting, and diarrhea, although symptoms were rarely grade 3 or grade 4.

In the combination group, 58% of patients required dose reductions because of AEs, most associated with pyrexia. Re-escalation was possible in most patients.

Full approval for the combination will depend on demonstration of improvements in PFS and survival from ongoing trials.

These early phase II data with combinations of BRAF and MEK inhibitors, in addition to the mechanistic understanding of pathways, have led to testing this combination in multiple phase III trials, such as NCT01584648, NCT01597908, and NCT01689519.[15] Combination therapy to address other mechanisms of resistance (e.g., via activation of the PI3K/Akt pathway) are in early-phase trials.

Multikinase inhibitors

Sorafenib

The multikinase inhibitor sorafenib has activity against both the vascular endothelial growth-factor signaling and the Raf/MEK/ERK pathway at the level of RAF kinase.

This agent had minimal activity as a single agent in melanoma treatment. Two large, multicenter, placebo-controlled, randomized trials of carboplatin and paclitaxel plus or minus sorafenib showed no improvement over chemotherapy alone as either first-line treatment or second-line treatment.[13,16]

KIT inhibitors

Early data suggest that mucosal or acral melanomas with activating mutations or amplifications in c-KIT may be sensitive to a variety of c-KIT inhibitors.[17-19] Phase II and phase III trials are available for patients with unresectable stage III or stage IV melanoma harboring the c-KIT mutation.

Chemotherapy

DTIC was approved in 1970 on the basis of overall response rates. Phase III trials indicate an overall response rate of 10% to 20%, with rare CRs observed. An impact on OS has not been demonstrated in randomized trials.[1,11,20-22] When used as a control arm for recent registration trials of ipilimumab and vemurafenib in previously untreated patients with metastatic melanoma, DTIC was shown to be inferior for OS.

Temozolomide (TMZ), an oral alkylating agent that hydrolyzes to the same active moiety as DTIC, appeared to be similar to DTIC (IV administration) in a randomized, phase III trial with a primary endpoint of OS; however, the trial was designed for superiority, and the sample size was inadequate to prove equivalency.[21]

The objective response rate to DTIC and the nitrosoureas, carmustine and lomustine, is approximately 10% to 20%.[20,23-25] Responses are usually short-lived, ranging from 3 to 6 months, although long-term remissions can occur in a limited number of patients who attain a CR.[23,25]

A randomized trial compared IV DTIC with TMZ, an oral agent; OS was 6.4 months for DTIC versus 7.7 months for TMZ (HR, 1.18; 95% CI, 0.92–1.52). While these data suggested similarity between DTIC and TMZ, no benefit in survival has been demonstrated for either DTIC or TMZ; therefore, demonstration of similarity did not result in approval of TMZ by the FDA.[21][Level of evidence: 1iiA]

An extended schedule and escalated dose of TMZ was compared with DTIC in a multicenter trial randomly assigning 859 patients (EORTC-18032 [NCT00101218]). No improvement was seen in OS or PFS for the TMZ group, and this dose and schedule resulted in more toxicity than standard-dose, single-agent DTIC.[26][Level of evidence: 1iiA]

Two randomized, phase III trials in previously untreated patients with metastatic melanoma (resulting in FDA approval for vemurafenib [11] and ipilimumab [1]) included DTIC as the standard therapy arm. Both vemurafenib (in BRAF V600 mutant melanoma) and ipilimumab showed superior OS compared with DTIC in the two separate trials.

Other agents with modest, single-agent activity include vinca alkaloids, platinum compounds, and taxanes.[23,24]

Attempts to develop combination regimens that incorporate chemotherapy (e.g., multiagent chemotherapy,[27,28] combinations of chemotherapy and tamoxifen,[29-31] and combinations of chemotherapy and immunotherapy [5,6,27,32-35]) have not demonstrated an improvement in OS.

A published data meta-analysis of 18 randomized trials (15 of which had survival information) that compared chemotherapy with biochemotherapy (i.e., the same chemotherapy plus interferon alone or with IL-2) reported no impact on OS.[36][Level of evidence:1iiA]

Palliative local therapy

Melanoma metastatic to distant, lymph node–bearing areas may be palliated by regional lymphadenectomy. Isolated metastases to the lung, gastrointestinal tract, bone, or sometimes the brain may be palliated by resection, with occasional long-term survival.[33-35]

Although melanoma is a relatively radiation-resistant tumor, palliative radiation therapy may alleviate symptoms. Retrospective studies have shown that symptom relief and some shrinkage of the tumor with radiation therapy may occur in patients with the following:[37,38]

Multiple brain metastases.

Bone metastases.

Spinal cord compression.

The most effective dose-fractionation schedule for palliation of melanoma metastatic to the bone or spinal cord is unclear, but high-dose-per-fraction schedules are sometimes used to overcome tumor resistance. (Refer to the PDQ summary on Pain for more information.)

Antiangiogenesis agents. Preclinical data suggest that increased vascular endothelial growth factor production may be implicated in resistance to BRAF inhibitors.[39]

Targeted therapy for specific melanoma populations.

In smaller subsets of melanoma, activating mutations may occur in NRAS (neuroblastoma RAS viral [v-ras] oncogene homolog) (15%–20%), c-KIT (28%–39% of melanomas arising in chronically sun-damaged skin, or acral and mucosal melanomas), and CDK4 (cyclin-dependent kinase 4) (<5%), whereas GNAQ is frequently mutated in uveal melanomas. Drugs developed to target the pathways activated by these mutations are currently in clinical trials.

Intralesional injections (for example, oncologic viruses).

Complete surgical resection of all known disease versus best medical therapy.

Isolated limb perfusion for unresectable extremity melanoma.

Systemic therapy for unresectable disease.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III melanoma, stage IV melanoma and recurrent melanoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of melanoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

be discussed at a meeting,

be cited with text, or

replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Melanoma Treatment are:

Russell S. Berman, MD (New York University School of Medicine)

Scharukh Jalisi, MD, FACS (Boston University Medical Center)

Alison Martin, MD (Martin and Associates Consulting)

Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

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